Glutamate is a transmitter that manages excitatory neurotransmission in the brain and known as an excitatory amino acid. It has been reported that when the excitatory amino acid is extracellularly released in a large amount, abnormal excitation of the central nerve occurs and leads to various diseases such as the brain/spinal cord damage, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's chorea; neurodegeneration; mental disorders; and functional motility disorders.
NMDA receptor, one of the glutamate receptors, is a tetrameric or pentameric assembly of a membrane protein having 4 membrane regions with a channel serving as an ion channel formed at the center. Usually, the channel is blocked by a magnesium ion. However, it is known that when the receptor is activated, sodium ions and calcium ions flow into a cell.
The NMDA receptor is involved in e.g., memory, learning and nerve development of mammalian brains. On the other hand, if the receptor is excited excessively, a large amount of calcium flows into a nerve cell and causes irreversible nerve-cell death in the brain. As a result, disorders such as motility disturbance, sensory disturbance and abnormal behavior may occur.
As a substance having an antagonistic action against NMDA receptor activity and specifically suppressing the activity of the receptor, memantine (general name: memantine hydrochloride) is known and widely applied as a therapeutic drug for Alzheimer's disease in a clinical setting in Europe and the U.S.A. Memantine attenuates calcium permeability through NMDA receptor in response to excessive release of glutamate, thereby protecting the nerve cells.
Furthermore, it is known that a kind of polyamine, spermine(N,N′-bis(3-aminopropyl)-1,4-diaminobutane) has a blockage action on NMDA receptor. However, the action of spermine on the NMDA receptor outside a cell strongly depends upon membrane potential. Spermine activates the receptor during depolarization (excitation) time and inhibits the activity of the receptor during hyperpolarization (resting) time (see, for example, Benveniste, M. et al. (Non-Patent Document 1), Rock, D. M. et al. (Non-Patent Document 2), Araneda, R. C. et al. (Non-Patent Document 3), Williams, K. et al. (Non-Patent Document 4) and Williams, K. (Non-Patent Document 5)). Because of such a two-track activity regulatory function, spermine is not suitably used as a medicinal drug.
Then, a spermine derivative has been proposed, which is designed by depriving it of the activity-promoting effect and maintaining and promoting only the inhibitory activity. As an example of the spermine derivative, N1-Dansyl-Spermine (Dansyl-SPM) represented by the formula (III) below may be mentioned (for example, Chao, J. et al. (see Non-Patent Document 6)).

In Dansyl-SPM, a dansyl group is bonded to a nitrogen atom at an end of spermine to produce sulfone amide, which suppresses the activity-promoting effect on NMDA receptor and enhances only the activity inhibitory effect. Dansyl-SPM exhibits higher affinity for NMDA receptor than memantine.
On the other hand, use of a polyamine derivative as a medicinal drug is suggested, for example, in the specification of European Patent Application Publication No. 1085011 (Patent Document 1), which discloses a polyamine derivative having an inhibitory action on polyamine transportation or a polyamine binding protein and suggests that a polyamine derivative may be used as an anticancer drug. Furthermore, as a spermine derivative, e.g., Dansyl-SPM mentioned above and N1-Tosyl-Spermine (Tosyl-SPM) represented by the formula (IV) below are mentioned as examples.
    Patent Document 1: European Patent Application Publication No. 1085011 (specification)    Non-Patent Document 1: Benveniste, M. et al., J, Physiol. (Lond.) 464: 131-163 (1993)    Non-Patent Document 2: Rock, D. M, et al., Mol, Pharmacol. 41: 83-88 (1992)    Non-Patent Document 3: Araneda, R. C. et al., Neurosci. Lett. 152: 107-112 (1993)    Non-Patent Document 4: Williams, K, et al., Mol. Pharmacol. 45: 803-809 (1994)    Non-Patent Document 5: Williams, K, Mol. Pharmacol. 46: 161-168 (1994)    Non-Patent Document 6: Chao, J. et al., Mol. Pharmacol. 51: 861-871 (1997)